This invention relates to imidazonaphthyridine and tetrahydroimidazonaphthyridine compounds, processes for making these compounds and intermediates used in their preparation. This invention additionally relates to pharmaceutical compositions containing imidazonaphthyridine and tetrahydroimidazonaphthyridine compounds. A further aspect of this invention relates to the use of these compounds as immunomodulators and for inducing cytokine biosynthesis in animals.
The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H-imidazo[4,5-c]quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, 94362 (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-c]quinolines.
Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of which are incorporated herein by reference. Although there continues to be interest in the imidazoquinoline ring system, as seen for example in WO 98/30562, there is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.
We have found a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Accordingly, this invention provides imidazonaphthyridine compounds of Formula I: 
wherein A, R1 and R2 are as defined hereinafter.
The invention also provides tetrahydroimidazonaphthyridine compounds of Formula II: 
wherein B, R1 and R2 are as defined hereinafter.
The compounds of Formula I and Formula II are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune reponse when administered to animals. This ability makes the compounds useful in the treatment of a variety of conditions, e.g. viral diseases and tumors that are responsive to such changes in the immune response.
The invention further provides pharmaceutial compositions containing a compound of Formula I or Formula II and methods of inducing cytokine biosynthesis in an animal and/or treating a viral infection in an animal by administering a compound of Formula I or Formula II to the animal.
In addition, methods of synthesizing compounds of Formula I and Formula II, and intermediates useful in the synthesis of these compounds are provided.
Further the invention provides a method of inducing interferon biosynthesis in an animal comprising the step of administering to said animal a compound of Formula I or Formula II in an amount effective to induce said interferon biosynthesis, and a method of treating a viral infection in an animal comprising the step of administering to said animal a compound of Formula I or Formula II in an amount effective to inhibit the viral infection.
As mentioned earlier, the invention provides compounds of Formula I: 
wherein
A is xe2x95x90Nxe2x80x94CRxe2x95x90CRxe2x80x94CRxe2x95x90; xe2x95x90CRxe2x80x94Nxe2x95x90CRxe2x80x94CRxe2x95x90; xe2x95x90CRxe2x80x94CRxe2x95x90Nxe2x80x94CRxe2x95x90; or xe2x95x90CRxe2x80x94CRxe2x95x90CRxe2x80x94Nxe2x95x90;
R1 is selected from the group consisting of:
hydrogen;
xe2x80x94C1-20 alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of:
-aryl;
-heteroaryl;
-heterocyclyl;
xe2x80x94Oxe2x80x94C1-20 alkyl,
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-aryl;
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-heteroaryl;
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-heterocyclyl;
xe2x80x94C1-20alkoxycarbonyl;
xe2x80x94S(O)0-2xe2x80x94C1-20 alkyl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-aryl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-heteroaryl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-heterocyclyl;
xe2x80x94N(R3)2;
xe2x80x94N3;
oxo;
-halogen;
xe2x80x94NO2;
xe2x80x94OH; and
xe2x80x94SH; and
xe2x80x94C1-20 alkyl-NR3xe2x80x94Qxe2x80x94Xxe2x80x94R4 or xe2x80x94C2-20 alkenyl-NR3xe2x80x94Qxe2x80x94Xxe2x80x94R4 wherein Q is xe2x80x94COxe2x80x94 or xe2x80x94SO2xe2x80x94; X is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR3xe2x80x94 and R4 is aryl; heteroaryl; heterocyclyl; or xe2x80x94C1-20 alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of:
-aryl;
-heteroaryl;
-heterocyclyl;
xe2x80x94Oxe2x80x94C1-20alkyl,
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-aryl;
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-heteroaryl;
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-heterocyclyl;
xe2x80x94C1-20 alkoxycarbonyl;
xe2x80x94S(O)0-2xe2x80x94C1-20alkyl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-aryl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-heteroaryl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-heterocyclyl;
xe2x80x94N(R3)2;
xe2x80x94NR3xe2x80x94COxe2x80x94Oxe2x80x94C1-20alkyl;
xe2x80x94N3;
oxo;
-halogen;
xe2x80x94NO2;
xe2x80x94OH; and
xe2x80x94SH; or R4 is 
wherein Y is xe2x80x94Nxe2x80x94 or xe2x80x94CRxe2x80x94;
R2 is selected from the group consisting of:
-hydrogen;
xe2x80x94C1-10 alkyl;
xe2x80x94C2-10 alkenyl;
-aryl;
xe2x80x94C1-10 alkyl-Oxe2x80x94C1-10-alkyl;
xe2x80x94C1-10 alkyl-Oxe2x80x94C2-10 alkenyl; and
xe2x80x94C1-10 alkyl or C2-10 alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-heteroaryl;
-heterocyclyl;
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently selected from the group consisting of hydrogen and C1-10 alkyl; and
each R is independently selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.
This invention also provides compounds of Formula II 
wherein
B is xe2x80x94NRxe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94; xe2x80x94C(R)2xe2x80x94NRxe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94; xe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94NRxe2x80x94C(R)2xe2x80x94 or xe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94NRxe2x80x94;
R1 is selected from the group consisting of:
-hydrogen;
xe2x80x94C1-20 alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of:
-aryl;
-heteroaryl;
-heterocyclyl;
xe2x80x94Oxe2x80x94C1-20 alkyl;
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-aryl;
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-heteroaryl;
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-heterocyclyl;
xe2x80x94C1-20 alkoxycarbonyl;
xe2x80x94S(O)0-2xe2x80x94C1-20 alkyl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-aryl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-heteroaryl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-heterocyclyl;
xe2x80x94N(R3)2;
xe2x80x94N3;
oxo;
-halogen;
xe2x80x94NO2;
xe2x80x94OH; and
xe2x80x94SH; and
xe2x80x94C1-20 alkyl-NR3xe2x80x94Qxe2x80x94Xxe2x80x94R4 or xe2x80x94C2-20 alkenyl-NR3xe2x80x94Qxe2x80x94Xxe2x80x94R4 wherein Q is xe2x80x94COxe2x80x94 or xe2x80x94SO2xe2x80x94; X is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR3xe2x80x94 and R4 is aryl; heteroaryl; heterocyclyl; or xe2x80x94C1-20 alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of:
-aryl;
-heteroaryl;
-heterocyclyl;
xe2x80x94Oxe2x80x94C1-20 alkyl,
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-aryl;
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-heteroaryl;
xe2x80x94Oxe2x80x94(C1-20alkyl)0-1-heterocyclyl;
xe2x80x94C1-20 alkoxycarbonyl;
xe2x80x94S(O)0-2xe2x80x94C1-20 alkyl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-aryl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-heteroaryl;
xe2x80x94S(O)0-2xe2x80x94(C1-20 alkyl)0-1-heterocyclyl;
xe2x80x94N(R3)2;
xe2x80x94NR3xe2x80x94COxe2x80x94Oxe2x80x94C1-20alkyl;
xe2x80x94N3;
oxo;
-halogen;
xe2x80x94NO2;
xe2x80x94OH; and
xe2x80x94SH; or R4 is 
wherein Y is xe2x80x94Nxe2x80x94 or xe2x80x94CRxe2x80x94;
R2 is selected from the group consisting of:
-hydrogen;
xe2x80x94C1-10 to alkyl;
xe2x80x94C2-10 alkenyl;
-aryl
xe2x80x94C1-10 alkyl-Oxe2x80x94C1-10-alkyl;
xe2x80x94C1-10 alkyl-Oxe2x80x94C2-10alkenyl; and
xe2x80x94C1-10 alkyl or C2-10 alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;,
-heteroaryl;
-heterocyclyl;
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently selected from the group consisting of hydrogen and C1-10 alkyl; and
each R is independently selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.
As used herein, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, and the prefix xe2x80x9c-alkxe2x80x9d are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. These cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl and adamantyl:
The term xe2x80x9carylxe2x80x9d as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term xe2x80x9cheteroarylxe2x80x9d includes aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, tetrazolyl, imidazo, and so on.
xe2x80x9cHeterocyclylxe2x80x9d includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiazolidinyl, and imidazolidinyl.
The aryl, heteroaryl and heterocyclyl groups may be unsubstituted or substituted by one or more substituents selected from the group consisting of C1-20 alkyl, hydroxy, halogen, N(R3)2, NO2, C1-20 alkoxy, C1-20 alkylthio, trihalomethyl, C1-20 acyl, arylcarbonyl, heteroarylcarbonyl, (C1-10alkyl)0-1-aryl, (C1-10alkyl)0-1-heteroaryl, nitrile, C1-20 alkoxycarbonyl, oxo, arylalkyl wherein the alkyl group has from 1 to 10 carbon atoms, and heteroarylalkyl wherein the alkyl group has from 1 to 10 carbon atoms.
The invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphs, and the like.
Preparation of the Compounds
Compounds of Formulas I and II wherein A is xe2x95x90Nxe2x80x94CRxe2x95x90CRxe2x80x94CRxe2x95x90 or B is xe2x80x94NRxe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94 and R, R1 and R2 are as defined above can be prepared according to Reaction Scheme I: 
Many 2-aminonicotinic acids of Formula III are known (see, for example, U.S. Pat. No. 3,917,624). The compound where R is hydrogen is commercially available. In step (1) of Reaction Scheme I a 2-aminonicotinic acid of Formula III is reacted with acetic anhydride by heating to provide a 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one of Formula IV. The compound of Formula IV where R is hydrogen is known and its preparation has been disclosed in U.S. Pat. No. 3,314,941 (Littell), the disclosure of which is incorporated herein by reference.
In step (2) of Reaction Scheme I a compound of Formula IV is reacted with sodium azide in a suitable solvent such as acetic acid to provide a tetrazolyl nicotinic acid of Formula V. The reaction conveniently may be run at ambient conditions.
In step (3) of Reaction Scheme I an acid of Formula V is esterified to provide a compound of Formula VI. The esterification may be carried out using conventional methods. For example, the acid may be esterified in acetone using potassium carbonate and ethyl iodide.
In step (4) of Reaction Scheme I a compound of Formula VI is cyclized to provide a tetrazolo[1,5-a][1,8]naphthyridin-5-ol of Formula VII. The reaction may be carried out by reacting the compound of Formula VI with an alkoxide in a suitable solvent, e.g., potassium ethoxide in N,N-dimethylformamide, at ambient conditions.
In step (5) of Reaction Scheme I a compound of Formula VII is nitrated using a suitable nitrating agent such as nitric acid to provide a 4-nitrotetrazolo[1,5-a][1,8]naphthyridin-5-ol of Formula VIII.
In step (6) of Reaction Scheme I a compound of Formula VIII is converted to a triflate of Formula IX. The reaction is preferably carried out by combining a compound of Formula VIII with a base, preferably a tertiary amine such as triethyl amine, in a suitable solvent such as dichloromethane and then adding trifluoromethanesulfonic anhydride. The addition is preferably carried out in a controlled manner, e.g., adding dropwise at a reduced temperature such as, for example, at about 0xc2x0 C. The product can be isolated by conventional methods or it can be carried on without isolation as described below in connection with step (7).
In step (7) of Reaction Scheme I a compound of Formula IX is reacted with an amine of formula R1NH2 where R1 is as defined above to provide a 4-nitrotetrazolo[1,5-a][1,8]naphthyridin-5-amine of Formula X. The reaction can be carried out by adding the amine to the reaction mixture resulting from step (6). The reaction can also be carried out by adding the amine to a solution of the compound of Formula IX and a tertiary amine in a suitable solvent such as dichloromethlane.
In step (8) of Reaction Scheme I a compound of Formula X is reduced to provide a tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine of Formula XI. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as ethanol.
In step (9) of Reaction Scheme I a compound of Formula XI is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine of Formula XII. Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R2 substituent in a compound of Formula XII. For example, diethoxymethylacetate will provide a compound where R2 is hydrogen and valeryl chloride will provide a compound where R2 is butyl. The reaction can be run in the absence of solvent, in a carboxylic acid such as acetic acid, or in an inert solvent in the presence of a carboxylic acid. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
In step (10) of Reaction Scheme I a compound of Formula XII is reacted with triphenylphosphine to provide a N-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine of Formula XIII. The reaction can be carried out by combining a compound of Formula XII with triphenylphosphine in a suitable solvent such as 1,2-dichlorobenzene and heating.
In step (11) of Reaction Scheme I a compound of Formula XIII is hydrolyzed to provide a 1H-imidazo[4,5-c][1,8]naphthyridin-4-amine of Formula XIV which is a subgenus of Formula I. The hydrolysis can be carried out by conventional methods such as by heating in a lower alkanol in the presence of an acid. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (12) of Reaction Scheme I a compound of Formula XIV is reduced to provide a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine of Formula XV which is a subgenus of Formula II. The reduction is carried out by suspending or dissolving a compound of Formula XIV in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure. The reaction can be conveniently carried out in a Parr apparatus. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Alternatively, as illustrated in step (13) of Reaction Scheme I, a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine of Formula XV can be prepared by reduction of a compound of Formula XII. The reduction is carried out by suspending or dissolving a compound of Formula XII in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure. The reaction can be conveniently carried out in a Parr apparatus. As above, the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Compounds of Formulas I and II wherein A is xe2x95x90CRxe2x80x94Nxe2x95x90CRxe2x80x94CRxe2x95x90 or B is xe2x80x94C(R)2xe2x80x94NRxe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94; R, R1 and R2 are as defined above can be prepared according to Reaction Scheme II. 
In step (1) of Reaction Scheme II a 3-aminoisonicotinic acid of Formula XVI is reacted with acetic anhydride by heating to provide a 2-methyl-4H-pyrido[3,4-d][1,3]oxazin-4-one of Formula XVII. The compound of Formula XVII where R is hydrogen is known and its preparation has been disclosed in Littell cited above.
In step (2) of Reaction Scheme II a compound of Formula XVII is reacted with sodium azide in a suitable solvent such as acetic acid to provide a tetrazolyl isonicotinic acid of Formula XVIII. The reaction conveniently may be run at ambient conditions.
In step (3) of Reaction Scheme II an acid of Formula XVIII is esterified to provide a compound of Formula XIX. The esterification may be carried out using conventional methods. For example, the acid may be esterified in acetone using potassium carbonate and ethyl iodide or by reacting with dimethylformamide diethyl acetal in a suitable solvent such as dichloromethane.
In step (4) of Reaction Scheme II a compound of Formula XIX is cyclized to provide a tetrazolo[1,5-a][1,7]naphthyridin-5-ol of Formula XX. The reaction may be carried out by reacting the compound of Formula XIX with an alkoxide in a suitable solvent, e.g., potassium ethoxide in N,N-dimethylformamide, at ambient conditions.
In step (5) of Reaction Scheme II a compound of Formula XX is chlorinated using a suitable chlorinating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride or preferably phosphorus oxychloride to provide a 5-chlorotetrazolo[1,5-a][1,7]naphthyridine of Formula XXI. The reaction can be carried out in an inert solvent or if appropriate in neat chlorinating agent. Preferred reaction conditions involve reaction in neat phosphorus oxychloride with heating at about 90xc2x0 C.
In step (6) of Reaction Scheme II a compound of Formula XXI is reacted with an amine of formula R1NH2 where R1 is as defined above to provide a tetrazolo[1,5-a][1,7]naphthyridin-5-amine of Formula XXII. The reaction can be carried out by heating with an excess of the amine.
In step (7) of Reaction Scheme II a compound of Formula XXII is nitrated using a suitable nitrating agent such as nitric acid to provide a 4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine of Formula XXIII. Preferably the reaction is carried out in acetic acid with mild heating and an excess of nitric acid.
In step (8) of Reaction Scheme II a compound of Formula XXIII is reduced to provide a tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine of Formula XXIV. Preferably the reduction is carried out using an excess of sodium hydrogensulfide in a suitable solvent such as acetic acid.
In step (9) of Reaction Scheme II a compound of Formula XXIV is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine of Formula XXV. Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R2 substituent in a compound of Formula XXV. For example, diethoxymnethylacetate will provide a compound where R2 is hydrogen and valeryl chloride will provide a compound where R2 is butyl. The reaction can be run in the absence of solvent, in a carboxylic acid such as acetic acid, or in an inert solvent in the presence of a carboxylic acid. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
In step (10) of Reaction Scheme II a compound of Formula XXV is reacted with triphenylphosphine to provide a N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine of Formula XXVI. The reaction can be carried out by combining a compound of Formula XXV with triphenylphosphine in a suitable solvent such as 1,2-dichlorobenzene and heating.
In step (11) of Reaction Scheme II a compound of Formula XXVI is hydrolyzed to provide a 1H-imidazo[4,5-c][1,7]naphthyridin-4-amine of Formula XXVII which is a subgenus of Formula I. The hydrolysis can be carried out by conventional methods such as by heating in a lower alkanol in the presence of an acid. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (12) of Reaction Scheme II a compound of Formula XXVII is reduced to provide a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine of Formula XXVIII which is a subgenus of Formula II. The reduction is carried out by suspending or dissolving a compound of Formula XXVII in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure. The reaction can be conveniently carried out in a Parr apparatus. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Alternatively, as illustrated in step (13) of Reaction Scheme II, a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine of Formula XXVIII can be prepared by reduction of a compound of Formula XXV. The reduction is carried out by suspending or dissolving a compound of Formula XXV in trifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide, and then subjecting the mixture to hydrogen pressure. The reaction can be conveniently carried out in a Parr apparatus. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Compounds of Formulas I and II wherein A is xe2x95x90CRxe2x80x94CRxe2x95x90CRxe2x80x94Nxe2x95x90 or B is xe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94C(R)2xe2x80x94NRxe2x80x94 and R, R1 and R2 are as defined above can be prepared according to Reaction Scheme III. 
In step (1) of Reaction Scheme III a 3-nitro[1,5]naphthyridin-4-ol of Formula XXIX is chlorinated using a suitable chlorinating agent such as phosphorus oxychloride to provide a 4-chloro-3-nitro[1,5]naphthyridine of Formula XXX. The reaction can be carried out by reacting a compound of Formula XXIX with phosphorus oxychloride in a suitable solvent such as N,N-dimethylformamide with mild heating (xcx9c55xc2x0 C.). The compound may be isolated by conventional methods or it can be carried on without isolation as described below in connection with step (2). The compound of Formula XXIX where R is hydrogen is known and its preparation has been disclosed in Hart, Journal of the Chemical Society pp. 212-214, (1956).
In step (2) of Reaction Scheme III a 4-chloro-3-nitro[1,5]naphthyridine of Formula XXX is reacted with an amine of Formula R1NH2 where R1 is as defined above to provide a 3-nitro[1,5]naphthyridin-4-amine of Formula XXXI. The reaction can be carried out by adding water then excess amine to the reaction mixture resulting from step (1) then heating on a steam bath. The reaction can also be carried out by adding excess amine to a solution of a compound of Formula XXX in a suitable solvent such as dichloromethane and optionally heating. The compound of Formula XXXI where R1 is hydrogen is known and its preparation has been disclosed in Wozniak et al, J. R. Neth. Chem. Soc. 102 (12), pp. 511-13 (1983).
In step (3) of Reaction Scheme III a 3-nitro[1,5]naphthyridin-4-amine of Formula XXXI is reduced to provide a [1,5]naphthyridine-3,4-diamine of Formula XXXII. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as ethyl acetate.
In step (4) of Reaction Scheme III a compound of Formula XXXII is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XXXIII. Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R2 substituent in a compound of Formula XXXIII. For example, diethoxymethylacetate will provide a compound where R2 is hydrogen and trimethylorthovalerate will provide a compound where R2 is butyl. The reaction can be run in the absence of solvent, in a carboxylic acid such as acetic acid, or in an inert solvent in the presence of an acid. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
Alternatively, step (4) may be carried out by (i) reacting a compound of Formula XXXII with an acylating agent; and then (ii) cyclizing the product. Part (i) involves reacting a compound of Formula XXXII with an acyl halide of formula R2C(O)X wherein R2 is as defined above and X is chloro or bromo. The reaction can be carried out by adding the acyl halide in a controlled fashion (e.g. dropwise) to a solution of a compound of Formula XXXII in a suitable solvent such as dichloromethane at a reduced temperature (e.g., 0xc2x0 C.). The resulting amide intermediate can be isolated by removal of the solvent. Part (ii) involves cyclizing the product of part (i) by reacting it with methanolic ammonia at an elevated temperature (e.g. 150xc2x0 C.) and pressure.
In step (5) of Reaction Scheme III a compound of Formula XXXIII is oxidized to provide a 1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide of Formula XXXIV using a conventional oxidizing agent that is capable of forming N-oxides. Preferred reaction conditions involve reacting a solution of a compound of Formula XXXIII in chloroform with 3-chloroperoxybenzoic acid at ambient conditions.
In step (6) of Reaction Scheme III a compound of Formula XXXIV is aminated to provide a 1H-imidazo[4,5-c][1,5]naphthyridin-4-amine of Formula XXXV which is a subgenus of Formula I. Step (6) involves (i) reacting a compound of formula XXXIV with an acylating agent; and then (ii) reacting the product with an aminating agent. Part (i) of step (6) involves reacting an N-oxide with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chlorides (e.g., benzenesulfonyl chloride, methanesulfonyl choride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred. p-Toluenesulfonyl chloride is most preferred. Part (ii) of step (6) involves reacting the product of part (i) with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving the N-oxide of Formula XXXIV in an inert solvent such as dichloromethane, adding the aminating agent to the solution, and then adding the acylating agent. Preferred conditions involve cooling to about 0xc2x0 C. to about 5xc2x0 C. during the addition of the acylating agent. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Alternatively step (6) may be carried out by (i) reacting a compound of Formula XXXIV with an isocyanate; and then (ii) hydrolyzing the product. Part (i) involves reacting the N-oxide with an isocyanate wherein the isocyanato group is bonded to a carbonyl group. Preferred isocyanates include trichloroacetyl isocyanate and aroyl isocyanates such as benzoyl isocyanate. The reaction of the isocyanate with the N-oxide is carried out under substantially anhydrous conditions by adding the isocyanate to a solution of the N-oxide in an inert solvent such as dichloromethane. The resulting product can be isolated by removal of the solvent. Part (ii) involves hydrolysis of the product from part (i). The reaction can be carried out by conventional methods such as heating in the presence of water or a lower alkanol optionally in the presence of a catalyst such as an alkali metal hydroxide or lower alkoxide.
In step (7) of Reaction Scheme III a compound of Formula XXXV is reduced to provide a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine of Formula XXXVI which is a subgenus of Formula II. The reduction is carried out by suspending or dissolving a compound of Formula XXXV in trifluoroacetic acid, adding a catalytic amount of platinum (IV) oxide, and then subjecting the mixture to hydrogen pressure. The reaction can be conveniently carried out in a Parr apparatus. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Certain functional groups recited in connection with R1 and R2 may be incompatible with some of the reagents of Reaction Schemes I, II and III. Compounds containing such functional groups can be prepared by those skilled in the art using well known methods of functional group protection and manipulation. For example, amine groups may be protected when necessary by derivatizing with di-tert-butyl dicarbonate.
Some compounds of Formula I or Formula II containing certain functional groups may be readily prepared from other compounds of Formula I or Formula II. For example, compounds wherein the R1 substituent contains an amide group may conveniently be prepared by reacting an acid chloride with a compound of Formula I or Formula II wherein the R1 substituent contains a primary amine. Likewise, compounds wherein the R1 substituent contains a urea group may be prepared by reacting an isocyanate with a compound of Formula I or Formula II wherein the R1 substituent contains a primary amine. Further, compounds wherein the R1 substituent contains a carbamate group may be prepared by reacting a chloroformate with a compound of Formula I or Formula II wherein the R1 substituent contains a primary amine.
Certain of the intermediate compounds useful in the preparation of compounds of Formula I and Formula II have not been previously described. Therefore, the invention also provides intermediate compounds useful in the preparation of compounds of Formula I and Formula II. The structural formulas of these novel intermediates are set forth below. These compounds have the following structural formulas: 
wherein R1, R2 and A are as defined above for compounds of Formula I and Formula II. 
wherein R, R1, and R2 are as defined above for compounds of Formula I and Formula II. 
wherein R, R1 and R2 are as defined above for compounds of Formula I and Formula II. 
wherein R7 is OH, halogen or NHR1 (and A and R1 are as defined above for compounds of Formula I) and R8 is H, NO2 or NH2. 
wherein A is as defined above for compounds of Formula I and R9 is H or C1-10 alkyl. 
wherein R and R1 are as defined above for compounds of Formula I and Formula II with the proviso that R1 is other than hydrogen, and R10 is NO2 or NH2.
Pharmaceutical Compositions and Biological Activity
Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of Formula I or Formula II as defined above in combination with a pharmaceutically acceptable carrier. As used herein, the term xe2x80x9ca therapeutically effective amountxe2x80x9d means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction or antiviral activity. Although the exact amount of active compound used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound as well as the nature of the carrier and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg of the compound to the subject. Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and so on.
The compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the Test Method set forth below. This ability indicates that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
Cytokines that are induced by the administration of compounds according to the invention generally include interferon (IFN) and tumor necrosis factor (TNF) as well as certain interleukins (IL). In particular, the compounds induce IFN-xcex1, TNF-xcex1, IL-1, 6, 10 and 12, and a variety of other cytokines. Among other effects, cytokines inhibit virus production and tumor cell growth, making the compounds useful in the treatment of tumors and viral diseases.
In addition to the ability to induce the production of cytokines, the compounds affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction. The compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes.
Compounds of the invention also have an effect on the acquired immune response. For example, although there is not believed to be any direct effect on T cells or direct induction of T cell cytokines, the production of the T helper type 1 (Th1) cytokine IFN-xcex3 is induced indirectly and the production of the Th2 cytokine IL-5 is inhibited upon administration of the compounds. This activity means that the compounds are useful in the treatment of diseases where upregulation of the Th1 response and/or downregulation of the Th2 response is desired. In view of the ability of compounds of Formula I and Formula II to inhibit T-helper-type 2 immune response, the compounds are expected to be useful in the treatment of atopy, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
The immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce cytokines such as IFN-xcex1 and TNF-xcex1, the compounds are particularly useful in the treatment of viral diseases and tumors. This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to viral diseases e.g. genital warts, common warts, plantar warts, Hepatitis B, Hepatitis C, Herpes Simplex Type I and Type II, molluscum contagiosm, HIV, CMV, VZV, cervical intraepithelial neoplasia, human papillomavirus and associated neoplasias; fungal diseases, e.g. candida, aspergillus, cryptococcal meningitis; neoplastic diseases, e.g., basal cell carcinoma, hairy cell leukemia, Kaposi""s sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin""s lymphoma, cutaneous T-cell lymphoma, and other cancers; parasitic diseases, e.g. pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, leishmaniasis; bacterial infections, e.g., tuberculosis, mycobacterium avium. Additional diseases or conditions that can be treated using the compounds of the invention include eczema, eosinophilia, essential thrombocythaemia, leprosy, multiple sclerosis, Ommen""s syndrome, rheumatoid arthritis, systemic lupus erythematosis, discoid lupus, Bowen""s disease and Bowenoid papulosis.
Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound of Formula I or Formula II to the animal. An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, INF-xcex1, TNF-xcex1, IL-1,6,10 and 12 that is increased over the background level of such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg. The invention further provides a method of treating a viral infection in an animal comprising administering an effective amount of a compound of Formula I or Formula II to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals. The precise amount will vary according to factors known in the art but is expected to be a dose of 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg.
The invention is further described by the following examples, which are provided for illustration only and are not intended to be limiting in any way.